Retinal dysplasia in dogs--a review

Retinal dysplasia is a developmental aberration of the neuroretina characterized by formation of retinal tubules, malformation rosettes and folding of the retina. Retinal dysplasia has been reported in Bedlington Terrier, Sealyham Terrier, Beagle, Labrador Retriever, English Cocker Spaniel, American Cocker Spaniel, English Springer Spaniel, Yorkshire Terrier and Rottweiler. A hereditary basis for retinal dysplasia has been proved or suggested for all breeds exhibiting retinal dysplasia except Beagle and Rottweiler. Ophthalmoscopically retinal dysplasia is characterized by vermiform streaks often radiating from the optic disc. The reflectivity of the tapetum is often altered in these areas. Accompanying retinal detachment or cataractous changes in the lens may be seen. Extensive retinal dysplasia and retinal detachment or cataract may result in visual impairment or blindness. Eyes exhibiting retinal dysplasia may be classified according to the number of layers from the retinal structure that are represented in the rosettes. Three-layer rosette. Two-layer rosette. Single-layer rosette. Primitive unilayer rosette. The etiology of retinal dysplasia includes viral disorders, irradiation, X-radiation, intrauterine trauma and heritable factors.     

Canine inherited retinal degenerations: update on molecular genetic research and its clinical application

Inherited retinal degenerations in the dog include generalised progressive retinal atrophy, retinal pigment epithelial dystrophy, congenital stationary night blindness and day blindness (hemeralopia). The clinical phenotype and pathology of these diseases closely resemble some types of human inherited retinal degeneration, in particular retinitis pigmentosa, one of the most common inherited causes of blindness in man. Molecular genetic investigations aim to identify the genetic mutations underlying the canine inherited retinal degenerations. Two major research strategies, candidate gene analysis and linkage analysis, have been used. To date, candidate gene analysis has definitively identified the genetic mutations underlying nine inherited retinal degenerations, each in a different breed of dog, and linkage studies have identified genetic markers for a further retinal degeneration which is found in at least six different breeds. This review outlines the research strategy behind candidate gene and linkage studies and summarises recent results in the search for genetic causes of canine inherited retinal degenerations. The aim is to increase awareness of this rapidly changing field and to show how the research can be used to develop genetic tests for these diseases and thereby reduce the incidence of inherited eye disease in dogs.     

Contrast-enhanced ultrasonography in the differentiation of retinal detachment and vitreous membrane in dogs and cats

Objectives : To evaluate contrast‐enhanced ultrasonography (CEU) and colour Doppler imaging (CDI) for detection of persistent vascularisation in retinal detachment. Methods : In 22 eyes, retinal detachment (n=13) and vitreous membranes (n=9) were confirmed by ophthalmological examination, during cataract surgery, by histopathology or after vitreoretinal surgery. Tentative diagnosis of retinal detachment or vitreous membrane was made using grey‐scale B‐mode ultrasonography. Assessment of retinal detachment was based on the presence or absence of vascularisation in the membranous structure using CDI and CEU. Results : Sensitivity, specificity, positive‐predictive value and negative‐predictive value of grey‐scale ultrasonography in differentiating retinal detachment from vitreous membrane were 92·3%, 66·6%, 80% and 85·7%. In 91% of eyes, colour Doppler assessment was unsuccessful due to the movement of the eye. Persistent vascularisation was demonstrated in all cases of retinal detachments with CEU. CEU was 100% accurate for detection and differentiation between retinal detachment and vitreous membrane. Clinical Significance : CEU is a useful clinical tool for the diagnosis of retinal detachment and vitreous membrane in dogs and cats.     

Viral vectors for targeting the canine retina: a review

Clinical trials are currently underway using gene therapy to treat retinal disease such as Leber congenital amaurosis (LCA). Viral vectors that have been utilized to target retinal cells include adenoviruses, lentiviruses, and recombinant adeno-associated viruses (rAAV). Of the three classes, rAAV vectors show the greatest promise for retinal gene therapy. Recent developments in virus technology such as the development of hybrid and capsid mutant rAAV vectors mean that specific retinal cells can be targeted and faster stronger transgene expression is now possible compared to that achieved with the first generation of vectors. Gene therapy trials in dogs have been very important in the development of therapy for RPE65 LCA which is currently in phase I/II clinical trials in humans. Recent successes in using gene therapy to treat canine achromatopsia, X-linked progressive retinal atrophy (PRA) and the more severe rapid degenerations such as rod-cone dysplasia type 3 may lead also to the translation to human clinical trials. Dogs have played and continue to play an important role as animal models for proof-of-concept studies of retinal gene therapy. As modifications and improvements in gene therapy protocols are made from experience gathered from human clinical trials perhaps gene therapy for the treatment of canine clinical patients will become available to veterinary ophthalmologists.     

Antibody-mediated retinopathies in canine patients: mechanism, diagnosis, and treatment modalities.

Antibody-mediated retinopathies may be widely present among the canine population. Early diagnosis and appropriate treatment are essential for visual preservation and reversal of blindness in these patients. The principal purpose of this review is to describe the mechanistic basis, clinical signs, diagnostic methods, and treatment options for retinal diseases causing sudden onset of blindness with absence of typical signs of intraocular inflammation or retinal degeneration-sudden acquired retinal degeneration syndrome and immune-mediated retinitis.     

Advances in the molecular understanding of canine retinal diseases

Retinal dystrophies are a common cause of blindness in purebred dogs. Progressive retinal atrophy, the canine equivalent of retinitis pigmentosa in humans, is the most common dystrophy. Molecular studies have led to the identification of the genetic defect underlying some forms of progressive retinal atrophy and the mapping of the chromosomal location of others. Additionally, the gene mutation that causes a severe retinal dystrophy in the briard, which is the equivalent of Leber congenital amaurosis in humans, has been identified. These advances have led to the development of DNA-based diagnostic tests for some retinal dystrophies, thus facilitating their eradication. The study of these dystrophies in dogs has also provided useful information about the equivalent diseases in humans. Recently, gene therapy has been used to restore vision to dogs with a retinal dystrophy due to a mutation in the RPE65 gene. Such studies are important in the quest to develop therapies for similar conditions in humans.     

Light at the end of the tunnel? Advances in the understanding and treatment of glaucoma and inherited retinal degeneration

Glaucoma and inherited retinal degeneration/dystrophy are leading causes of blindness in veterinary patients. Currently, there is no treatment for the loss of vision that characterizes both groups of diseases. However, this reality may soon change as recent advances in understanding of the disease processes allow researchers to develop new therapies aimed at preventing blindness and restoring vision to blind patients. Elucidating the molecular mechanisms of retinal ganglion cell death in glaucoma patients has led to the development of neuroprotective drugs which protect retinal cells and their function from the disastrous effects of elevated pressure. Identification of the genetic mutation responsible for inherited degenerations and dystrophies of the outer retina has enabled researchers using gene therapy to restore vision to blind dogs. Other patients may benefit from retinal transplantation, stem cell therapy, neuroprotective drugs, nutritional supplementation and even retinal prostheses. It is possible that soon it will be possible to restore sight to some blind patients.     

Fractal analysis of retinal vessel patterns in ophthalmically normal dogs

OBJECTIVE: To study the applicability of the fractal dimension as a parameter for describing retinal vessel patterns in ophthalmically normal dogs. PROCEDURES: The following strategy was adopted: (i) development of an experimental procedure to obtain digitalized photographs of the fundus; (ii) development of software to segment retinal vessel images and calculate the box-counting and radius of gyration fractal dimensions of the retinal vessels and diffusion-limited aggregation (DLA), a process with similar characteristics to retinal vessel morphology, and (iii) establishment of a standard curve for the fractal dimensions of segmented vessels. RESULTS: Digitalized photographs of the fundus showed an adequate contrast between the vessels and the rest of the fundus for numerical analysis. The software developed produced a binary image of the retinal vessels permitting calculation of the fractal dimension. The mean values of the fractal dimensions calculated by the methods of box-counting and radius of gyration for the DLA were significantly different (t = -40.33, P approximately 0). The radius of gyration method was found to be more suitable for documenting the dimension of the DLA and, consequently, of the dog's retinal vessels. CONCLUSION: This methodology may be useful to differentiate between normal and pathologic states of canine retinal vascularization.     

鲫鱼和斑马鱼视网膜结构的比较组织学研究

为探讨鲫鱼(Carassius auratus)和斑马鱼(Brachydanio rerio)视网膜组织结构与其生活环境的适应关系,对这2种鱼视网膜各层厚度、3个核层的胞核层数进行了测量,并对数据进行了统计分析。结果表明:鲫鱼和斑马鱼视网膜均由4层细胞构成,在光镜下共分为10层。鲫鱼视网膜平均厚度196.57μm,斑马鱼视网膜平均厚度167.57μm。斑马鱼的视网膜内核层的细胞数目比外核层多,而鲫鱼的视网膜外核层细胞数目多于内核层数目。鲫鱼和斑马鱼这2种鱼类视网膜结构的差异,与其各自的生活环境相适应。     

Microvasculature of the rat eye: scanning electron microscopy of vascular corrosion casts

Methylmethacrylate castings of the eye microvasculature were prepared from 10 Spargue-Dawley rats and studied by electron microscopy. The choroidal arterioles are larger in diameter than retinal arterioles, and have a shorter course to choroidal capillaries than retinal arterioles to retinal capillaries. Retinal capillaries are extremely thin in diameter and form a sparse retinal capillary network. The choriocapillaris is large and sinusoid-like, forming a compactly arranged network in the choroid. These differences in the microvasculature between the choroid and retina help explain the differences in ocular hemodynamics; that is, the blood flow in the choroid is faster than that in the retina. Capillaries of the iris show a zigzag configuration, which may be an accommodation for dilation and constriction of the pupil. Capillaries of the ciliary body are of large diameter forming leaf-like configurations, presumably to contribute to the secretion of the aqueous humor. Capillaries of the conjunctiva exhibit a somewhat coiled configuration, the arrangement of which reduce tension of the conjunctiva vessels caused by eyeball movement. Intra-arterial cushions, which control blood flow at the branching sites, are found in both choroidal or retinal arterioles.     

Multifocal retinopathy of Great Pyrenees dogs

Forty-four related Great Pyrenees dogs were examined ophthalmoscopically. Focal retinal elevations, multiple gray-tan-pink subretinal patches, and discrete areas of tapetal hyper-reflectivity were seen in 19 dogs, ranging from 13 weeks to 10 years of age. These lesions varied in size from focal spots that were barely visible with the indirect ophthalmoscope to areas that were larger than the optic disc. Complete blood cell counts, serum biochemical profiles, urinalyses, and blood pressure measurements were completed on four affected dogs and all were within normal reference ranges. Photopic and scotopic electroretinography was completed and the a-wave and b-wave amplitudes and latencies were similar for affected and age-matched nonaffected Great Pyrenees and other normal dogs. Electroretinograms that were examined twice during a 3-year period on three affected adult dogs did not reveal significant progressive deterioration of the a or b-wave parameters. Fluorescein angiography was completed on four affected dogs of ages 1 (n = 2), 5, and 6 years. These angiograms were repeated in three of these dogs 1 year later. The blood ocular barrier was intact in these dogs but there was blocked choroidal fluorescence. Postmortem examination, light microscopy, scanning and transmission electron microscopy were performed on three affected puppies and two affected adult dogs. These examinations revealed that the lesions in the puppies were limited to bilateral multiple areas of retinal pigment epithelial vacuolation, hypertrophy, and apparent separation from Bruch's membrane, and multiple serous retinal detachments. The affected adult dogs had focal retinal degeneration and retinal pigment epithelial hypertrophy, hyperplasia and pigmentation. Pedigree analysis and test mating confirm that this condition is inherited, probably as an autosomal recessive trait. This condition develops at approximately 13 weeks of age and the focal areas of retinal detachment and retinal pigment epithelial vacuolation progress to permanent and stable focal areas of retinal degeneration, and retinal pigment epithelial hypertrophy and pigmentation.     

Feline retinal degeneration: clinical experience and new findings (1994-1997)

A retrospective case series of 26 cats with diffuse retinal degeneration is presented. The most common presenting complaints included bumping into objects, dilated pupils, and reluctance to jump. Ophthalmic examination findings were consistent with those reported in dogs with progressive retinal atrophy. Breed predilection of the Siamese cat was observed. Cats with primary retinal degeneration presented late in the clinical course of their disease, when vision loss was severe. Early symptoms such as night blindness and secondary ocular complications (i.e., cataract and retinal detachment), reported in dogs with progressive retinal degeneration, were not observed in this study. All cats showed excellent adaptive capabilities to blindness.     

Retinal degeneration in the dog and cat

Retinal degenerations in the dog and cat are an important cause of blindness in these species. Particularly in the dog, many retinal degenerations, collectively called progressive retinal atrophy, seen in clinical practice are inherited. The clinical signs, electrophysiological findings, pathology, and underlying biochemical defects in the retina vary from breed to breed. Specific categories of inherited retinal degeneration are now recognized, and classified into early onset photoreceptor dysplasias, late-onset retinal degenerations, or retinal degenerations secondary to primary RPE dystrophy. As new inherited retinal degenerations are reported in different breeds they can generally be assigned to one these categories. Other causes of retinal degeneration include nutritional deficiencies, glaucoma, inflammation, ischemia, and toxins. Idiopathic retinal degeneration occurs in the dog with some frequency.     

SLO angiography: arterio-venous filling times in monkey and minipig

Confocal scanning laser ophthalmosocope (cSLO) is a new technique which enables ocular fundus image recording and dynamic retinal angiography to be performed. The ocular fundus image is acquired sequentially, point by point, and is reconstructed on a video monitor at the rate of 25 images per second. The aim of this paper is to evaluate the feasibility of measuring retinal arterio‐venous filling times (AVFT) with a I + Tech cSLO. Three young adult cynomolgus monkeys and three young adult Göttingen minipigs were used as experimental models. All animals were anesthetized using a zolazepam + tiletamine mixture injected intramuscularly; heart rate and rectal temperature were monitored and corneal irrigation was regularly performed. For all subjects, prior to examination, hematocrit and globe axial length were measured. The images were recorded, stabilized and analyzed. The retinal examination consisted of retinal images with 40° field cSLO, retinal fluorescein angiography and arterio‐venous 50% filling time measurements. For each subject all images were easily recorded while keeping the animals in a normally lighted room without having to use any additional optical device. AVFT using an I + Tech cSLO is easily performed in monkeys and minipigs. AVFT measurements in minipigs and monkeys are similar. These results suggest that minipigs can replace monkeys as an experimental species for AVFT investigations.     

Comparative retinal ganglion cell and optic nerve morphology

The optic nerve is divided in four regions: intraocular, intraorbital, intracanalicular, and intracranial. The vertebrate retinal ganglion cells are classified by morphology, physiology and soma size. Species differences and similarities occur with retinal ganglion cells. Alpha retinal ganglion cells have large somata, large dendritic fields, large-diameter axons, and are most dense in the peripheral retina. Beta retinal ganglion cells have smaller diameter somata, smaller dendritic fields, small diameter axons, and predominate in the central retina. Gamma retinal ganglion cells are a heterogenous class of cells and have small diameter axons, and slow axon conduction velocities. The spatial distribution and organization of the retinal ganglion cells extends retinotopically through the nerve fiber layer, optic nerve, optic chiasm, optic tract, lateral geniculate nucleus, and visual cortex. The retinal nerve fiber layer thickness decreases from the optic disk toward the periphery of the retina. The retrobulbar optic nerve axon counts and axon density vary by species, with larger nerves having higher axon counts. Decussation of the optic nerve axons at the optic chiasm varies with 100% decussation in most birds and fish, 65% in cats, 75% in dogs, 80–90% in large animals, and 50% in primates. Centrifugal axons also occur in the optic nerve and may represent a method by which the brain can influence retinal activity.     

Ocular fundus images with confocal scanning laser ophthalmoscopy in the dog, monkey and minipig

Confocal scanning laser ophthalmoscopy (CSLO) is a new technique that enables ocular fundus image recording and retinal dynamic angiography to be performed. The ocular fundus image is acquired sequentially, point by point, and is reconstructed on a video monitor at the rate of 25 images per second. The feasibility of performing both ocular fundus image recordings and retinal angiography image recordings were tested on two dogs, two monkeys and two minipigs using a 40° field I + Tech CSLO. Fundus area of each dog, monkey and minipig were examined without any additional optical devices. The ocular fundus and angiography images were recorded, stabilized and analyzed under the same conditions. For each species, all images were easily recorded without any additional optical device in a lighted room and the morphology of the retinal images generated was similar to those obtained with a camera or angiography of higher resolution. Capillary phase or venous times are presented. Image recording at 25 frames/second enabled more retinal dynamics to be demonstrated than with use of regular angiography. This technique is noninvasive and easy to perform if the eye is fixed and eyelids maintained open. It also allows exploration of retinal microvascularization and could be utilized for clinical, pharmacologic and toxicologic investigations as well.     

The geographic form of retinal dysplasia in dogs is not always a congenital abnormality

To examine the congenital nature of the geographic form of focal/multifocal retinal dysplasia, we carried out a retrospective analysis of the medical records of dogs produced in a closed colony of service dogs who receive very thorough ophthalmologic examinations early in their life, and later, when they return for training. Medical records were reviewed from all dogs produced by The Seeing Eye, Inc. between October 1991 and September 1998, and which had a diagnosis of geographic retinal dysplasia coded. We identified 23 dogs of five different breeds or interbreed crosses that comprise the breeding and production program (Golden Retrievers, German Shepherds, Labrador Retrievers, Labrador Retriever/Golden Retriever cross and German Shepherd/Labrador Retriever cross) in which the results of at least two complete ophthalmic examinations were documented, the first before 10 weeks of age, and the second when the dog was a young adult. Of the 23 dogs, only one was identified as affected with the geographic form of retinal dysplasia when examined at 5–6 weeks of age. The remaining dogs were normal. Our findings indicate that, in most cases, the geographic form of retinal dysplasia is not present in dogs prior to 10 weeks of age. These findings indicate the need to revise recommendations for early screening of dogs for retinal dysplasia.     

Outer retinal degeneration in two closely related Goeldi's monkeys (Callimico goeldii)

This case report comprises studies of four Goeldi's monkeys (Callimico goeldii) from the same enclosure. Globe samples from two related C goeldii (the female C goeldii and her male offspring) were available for a histopathological evaluation. Both cases presented histopathologically evident outer retinal degeneration with differences in severity. There was marked outer retinal atrophy characterized by loss of the outer and inner photoreceptor segments, and depletion of the outer retinal nuclear layer. Furthermore, we report a reduction in the thickness of the outer retinal plexiform, inner retinal nuclear layer, and inner retinal plexiform layer in these C goeldii monkeys. To the authors’ knowledge, these findings have not yet been reported in wild‐ or captive‐bred population of C goeldii.     

Recent advances in understanding the spectrum of canine generalised progressive retinal atrophy

Canine generalised progressive retinal atrophy (gPRA) is a large and ever-increasing collection of naturally occurring, heterogeneous, progressive disorders. Most are inherited in an autosomal recessive manner and new, breed-specific forms continue to be described. The gPRAs cause photoreceptor cell death and subsequent retinal degeneration, culminating in blindness. In humans, similar inherited retinal dystrophies are recognised as retinitis pigmentosa and macular dystrophy. Molecular biological studies have revealed disease-causing mutations in several genes in humans and also in mice with retinal dystrophies. Recently, molecular genetic techniques have identified the cause of one form of gPRA in Irish setters while important candidate genes have been investigated in other breeds. Identification of mutations responsible for different forms of gPRA allows carrier and pre-degenerate animals to be detected using DNA-based tests. Such genetic tests will greatly facilitate the eradication of these diseases in different breeds.